1 EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable Artery coronary disease) is the largest and longest study ever conducted in patients with stable coronary disease. It was announced at ESC in Vienna on the 31st of August 2003 during an official hotline session. EUROPA is considered as a reference study for the initiation of the ACEI perindopril 8 mg once daily as chronic treatment in all patients with stable coronary artery disease.

2 Studientrends mit ACE HemmernWirksamkeitBehandlung nachEreignissenPrävention vonEreignissenCONSENSUS 1SOLVDAIRESAVETRACEHOPEPEACEThe clinical trials with ACE inhibitors in coronary artery disease patients over the years have proved their benefits in the “treatment” of patients right after the ischemic event (CONSENSUS, SOLVD, AIRE, SAVE, TRACE) and it was less proved on the “prevention” of secondary events (EUROPA, HOPE, PEACE), or even failed to prove (QUIET).GISSI-3ISIS-4Administrative Zeitnach EreignissenvorherQUIETCONSENSUS 2Diese Studien konnten keinen Erfolg nachweisen

3 Benefits der ACE HemmungSOLVDSAVEAIRETRACEHOPESOLVD(prev)So far, the benefit of ACE inhibitors were extensively investigated in large cohort of ishemic heart disease patients: post MI, LVSD with EF<40%, HF. The difference between these trials lies in the type of patients selected for each respective trial, which are actually patients of high risk.Coronary artery disease is a progressive condition involving patients with lower and higher risk levels. For cardiologists, according to the investigators from the EUROPA trial, patients involved presented all-risk coronary patients in comparison to other trials conducted in this area, which were patients considered as high risk patients.So, EUROPA was aiming to resolve the question on the benefits of ACE inhibition in the treatment of all risk stable coronary artery disease patients.ALLE KHK PATIENTEN

4 Sekundäre Prävention von KHK Warum ACE Hemmung?ANGIOTENSINOGENKININOGENRenin++KallikreinAngiotensin IBradykininACE++Angiotensin IIDesaktivierungB2RezeptorATRezeptorenEndothelialzelleThe rationale of the possible benefits of an ACEI in the treatment of coronary artery disease is based on their anti ischemic properties linked to their mode of action.Angiotensin II (A II) plays a significant role in the mechanisms which underlie the atherosclerotic process: vasoconstriction and cell proliferation.Angiotensin-converting enzyme (ACE) inhibitors, such as perindopril, interrupt the production of A II, leading to antiproliferative and anti atherogenic effect.On the other hand, ACE inhibitors counteract the breakdown of bradykinin. A substance, which is responsible for the improvement in endothelial function, leading to vasodilation and growth inhibition. Bradykinin stimulates nitric oxide (NO) production and prostaglandin release from the endothelium. NO production and prostaglandin release yield beneficial vasodilatory, growth-inhibitory, antiatherogenic, antithrombotic, anti-inflammatory, and antioxidant effects.GlatteGefäß-muskelzelleVasokonstriktionZellproliferationVasodilationWachstumshemmungCMF Learning Systems in 2000, “Courtesy CM Ferrario, MD”

5 Sekundäre Prävention von KHK Warum ACE Hemmung?BRADYKININ SYSTEMANGIOTENSIN SYSTEMKininogenAngiotensinogenKallikreinReninAng IEndothelBradykininACEHemmerWirkung++ACE Thrombo-aggregation+(Enzym)Ang IIProstaglandinNOIndeed, looking more closely at the very important formation of bradykinin and pharmacological mode of action of ACEIs, we can conclude that bradykinin is one of the most important consequence of ACE inhibition.Bradykinin stimulates the release of NO from the endothelium, which not only dilates the vessel but also reduces platelet aggregation, the activity of white cells, and smooth muscle cell hypertrophy, all of which result from the activities of angiotensin II.Damage to the endothelium by smoking, hypercholesterolemia, diabetes, hypertension, or superoxides inhibits NO release, allowing angiotensin II to exert the harmful effects, as represented on the left side of the figure.SMC = glatte MuskelzellenFGF = Fibroblasten Growth FactorPDGF = Platelet Derived Growth FactorInaktive PeptideVerstärkung der sympathischen AktivitätVasokonstriktion SMCMitogeneseVasodilatationFGFPDGF Aldosteronfreisetzung

6 Endotheliale Dysfunktion: Plaques im FrühstadiumPermeabilitäts-steigerungEintritt von LeukozytenLeukozyten-adhäsionThe earliest changes that occur within the dysfunctional endothelium include:Increase of the permeability of the endothelium to lipoproteins and plasma constituents. This alteration is mediated by nitric oxide, angiotensin II, endothelin and other compounds.Leukocyte adhesion molecules are produced in greater quantity, thus increasing the uptake of leukocytes and their adhesion to the vessel wall.Adapted from Ross R. N Engl J Med 1999; 340:

7 Endotheliale Dysfunktion: Plaques im SpätstadiumMigration glatter Muskelz.Lipid- akkumulationEnt-zündungPlättchen-aggregationEintritt von LeukozytenAs the dysfunctional endothelium progresses from early to more mature stages of atherosclerotic lesions, abnormal activity within the blood vessel continues:A fatty streak is formed within the vessel wall (lipid accumulation). Later, smooth muscle cells begin to migrate into the developing plaque.Leukocytes continue to adhere to the endothelium and after penetration move into the vessel wall.Inflammatory response in the atherosclerotic lesion starts.Platelets adhere to the dysfunctional endothelium contributing to the migration and proliferation of smooth muscle cells and monocytes, but also to platelet aggregation. Platelets accumulating on the vessel wall contribute to thrombus formation.As the atherosclerotic plaque progresses to late stages, a fibrous cap forms over the plaque and walls of the lesion from the vessel lumen. This fibrous cap may then become unstable and rupture causing thrombus formation, and often, CV events.Adapted from Ross R. N Engl J Med 1999; 340:

12 Hohe Affinität zu Gewebs-ACE bei KHK-ErkranktenKontrolleACE Up-Regulierung während des ischämischen ZustandesPerindoprilHemmung des endothelialen und adventitialen ACEPerindopril has a very high tissue and plasma ACE affinity, as proven for the first time ever with an ACEI in humans suffering from coronary artery disease. Zhuo et al. studied the in vivo effects of ACE inhibition with perindopril on cellular expression of ACE, in human blood vessels using quantitative in vitro autoradiography and immunocytochemistry.Perindopril decreased plasma ACE by 70% and the plasma angiotensin II to angiotensin I ratio by 57%, and reduced vascular ACE to approximately 65% of control levels in both endothelium and adventitia.Perindopril inhibits both endothelial and advential ACE, this being further proof for reversing endothelial dysfunction, a key role player in the manifestation of cardiovascular diseases and their complications. This is one of the main reasons supporting its choice in the EUROPA study.Zhuo JL et al. Hypertension. 2002;39:

18 Verbesserte Koronarreserve*P = 0.001n = 14+ 67%*Baseline2.112 Monate Behandlung mit Perindopril 4 mg3.5As a result, the coronary reserve increased by 67%. Also, the LV muscle mass index significantly decreased by 11% after a 12-month perindopril treatment. Percent of increase in coronary reserve was more than expected by regression of LVH alone. Regression of fibrosis was demonstrated by perindopril in the non-pressure overloaded right ventricle and independently from local myocyte size. It seems to be due to direct/chronic effects of perindopril on collagen metabolism.Perindopril 4 to 8 mg, once daily, reverses both interstitial fibrosis and LV mass in patients with LVH and significantly restores coronary flow reserve in the long term treatment independently of its anti-hypertensive efficacy.Schwartzkopff B et al. Hypertension. 2000;36:

19 Verstärkte FibrinolyseFreisetzung von Tissue-type Plasminogen Aktivator (tPA) in der koronaren Zirkulation700Perindopril 4 mg/Tag500***Losartan 50 mg/TagKontrolletPA Freisetzung(ng/min/100 mL)300Hypertoniepatienten (n=34)100* P<0.05 vs Kontrolle** P<0.05 vs LosartanIt has been confirmed that in hypertensive and cardiovascular disease the reduced levels of tissue-type plasminogen activator (t‑PA), are contributing to thrombus formation. This plays a role in the pathogenesis of acute myocardial infarction and stroke. In a recent trial which compared the effects of perindopril and losartan on fibrinolytic balance in coronary artery circulation of the patients with atypical chest pain and hypertension, perindopril increased t-PA enhanced by bradykinin significantly more than losartan.It was concluded that perindopril may have a greater potential to enhance the bradykinin-induced coronary release of t-PA than losartan.Perindopril increases t-PA level and restores fibrinolytic balance acting on a major component of the myocardial ischemia process.Matsumoto T, Minai K, Horie H, et al. J Am Coll Cardiol. 2003;41:-1000.20.62.0Bradykinin (µg/min)Minai K et al. Japanese Circulation Journal. 2001;65(suppl I-A)

21 Anti-ischämische WirksamkeitST-SEGMENT DEPRESSIONBELASTUNGS-INDUZIERTE VENTRIKULÄRE SYSTOLISCHE DYSFUNKTIONVeränderung ST-Segment (mm)Left ventricular motion scoreP < 0,05- 39%6- 42%P < 0,0552,542%39 %4231,521Finally and as a final proof of perindopril’s choice for EUROPA it is interesting to look after its anti-ischemic efficacy, as recently proven in humans suffering from stable angina.After 3 months of treatment, perindopril given at the same dosage as used in EUROPA, that is to say 8 mg significantly reduces the time to ST-segment depression, as well as exercise-induced left ventricular systolic dysfunction.A linear relationship exists between the inhibition of plasma ACE by perindopril and the increase in bradykinin concentration. This high concentration is thought to be involved in the anti-ischaemic effects obtained with perindopril.This further emphazises its choice to conduct the EUROPA trial.10,5vorher3 Monate Perindoprilvorher3 Monate PerindoprilMorishita T et al. Jpn J Pharmacol. 2002;88:

23 Exzellente Verträglichkeit – auch bei fragilen PatientenPerindoprilPlazeboBlutdruck (mmHg)Perindopril senkt den RR während die zerebrale Durchblutung erhalten bleibtCoversyl once daily maintains cerebral blood flow in patients with acute ischemic stroke. There is an obvious theoretical concern that Bp lowering agent may also cause an adverse reduction in cerebral blood flow. In patients with already compromised cerebral circulation (ie, those who have had a stroke) this would clearly be highly undesirable. However it appears Coversyl provides BP controls without any adverse effects on cerebral blood flow.In a study of 28 patients with acute stroke and hypertension, between 48 hours and 7 days after a stroke, patients were randomized to either Coversyl once daily or placebo. The comparison with the placebo curve is particularly important in the context of a stroke because of the spontaneous wide variations of blood pressure in the acute phase ( first weeks). Cerebral blood flow was calculated from internal carotid artery Doppler ultrasound measurements. These measurements were undertaken 3 times: before intake of Coversyl, during the first 24 hours, and then repeated after 2 weeks. The results show that Coversyl reduces BP while maintaining cerebral blood flow.Zeit nach der EinnahmeDyker AG, Grosset DG, Lees KR. Stroke. 1997;28:

26 Studien-Design Randomisierung Run-in Periode Follow-upPerindopril 8 mg 1x täglichPerindopril4 mg8 mgPlazebo-1-1/21224364860MonateRandomisierungAfter the run-in period of 2 weeks patients received 4 mg of perindopril once daily in the morning in addition to their usual medication.At 4 weeks, the thrid visit, patients were randomized double-blind to perindopril 8 mg or placebo, and continued their treatment until the last patients included complete the 4-year follow-up period.Run-in PeriodeFollow-up

27 PatientenauswahlkriterienMännlich oder weiblich > 18 Jahre altNachgewiesene koronare Herzkrankheit (=KHK)Keine geplante RevaskularisierungKeine klinischen Zeichen einer HerzinsuffizienzAccording to these selection criteria, some important points can be highlighted: the patient profile is very close to the general population met in clinical practice in terms of age and risk factors.Patients include were older than 18 years, had documented coronary disease, were not scheduled for revascularisation and had no clinical signs of heart failure.

28 Nachgewiesene KHK Vorangegangener MI > 3 MonatePCI / CABG > 6 MonateAngiographischer Nachweis einer KHK ( 70% Stenose mindestens einer Koronararterie)Männliche Angina pectoris Patienten:positiver Belastungs- oder StresstestEUROPA includes 100% of patients with proven 100% coronary artery disease.12,218 patients aged 26 to 89 years (mean age 60 years) without heart failure were recruited and randomised if they had documented CAD, which was defined as either:A history of previous MI at least three months before selectionA history of PTCA or CABG at least 6 months oldSignificant coronary stenosis on coronary angiogramIn males with a history of chest pain, by a positive exercise test, stress echo or scintiography

30 Patienten RekrutierungAbgeschlossen6.1076.108Perindopril6.110PlazeboRandomisiert12.218Nicht randomisiert1.437Einschluss13.655Patients were followed up at 3, 6, and 12 months, and every 6 months thereafter. After randomisation, withdrawals from treatment were similar to those for placebo, and only 3 patients were lost to follow up amongst 12,218 patients.

31 424 Zentren: Patienten10217614113057125121761159430039928551189017222068177227713420965197830EUROPA trail is a true pan-European trial.Therefore, the results were applicable across all Europe, including 12,218 patients that were randomised from 424 centers in 24 Europeen countries, involving 525 investigators.

33 Baseline CharakteristikaPerindopril(mittlerer  SD)PlazeboAlter (Jahre)60  9männlich (%)8685Gewicht (kg)81  1280  12HF (bpm)68  10SBD (mmHg)137  16137  15DBD (mmHg)82  8The analysis of the baseline characteristics of patients recruited into the study showed that:Patients were at least 18 years without clinical evidence of heart failure and with evidence of coronary artery disease. In average they were 60 years old which is not old for coronary artery disease. They were largely men: 86%, weight: 81+12, heart rate: and they had normal blood pressure. Importantly, there were no differences between these two groups, perindpril and placebo, almost identically matched.

34 Anamnese Perindopril Plazebo Myokardinfarkt 64.9 64.7(%)PlazeboMyokardinfarkt64.964.7Revaskularisierung54.755.2Schlaganfall / TIA3.43.3Herzinsuffizienz1.31.2Periphere Gefäßkrankheiten7.17.4There were 65% of patients with previous history of MI, 83% of those with MI was more than 1 year in the past, 1/3 of them had an MI 5 years before study started. Half of the patients randomised had revascularisation, and small % of patients had peripheral vascular disease, history of stroke or TIA and 1.3 had heart failure as it was the exclusion criteria, all equally balanced between perindopril and placebo group.

35 Risikofaktoren Perindopril Plazebo Hypertonie 27.0 27.2(%)PlazeboHypertonie27.027.2Diabetes Mellitus11.812.8Hypercholesterinämie63.3Raucher15.415.1Patients randomised in EUROPA trial involved: hypertensive patients, which presented 27% of the study population, 11.8% of patients had diabetes, 63.3% were hypercholesterolemic and 15.4% declared themselves as smokers.Again, a very balanced population was maintained between perindopril and placebo groups of patients.

36 Baseline Medikation Perindopril Plazebo Plättchenhemmer 91.9 92.7(%)PlazeboPlättchenhemmer91.992.7-Blocker62.061.3Lipidsenker57.857.3Nitrate42.843.0Ca-Antagonisten31.731.0Diuretika9.19.4Orale Antikoagulantien4.44.2Of particular importance when it comes to interpretation of this study is the background treatment.Demographic data clearly demonstrate that the EUROPA patients were receiving perindopril or placebo on top of optimal preventive therapy. Most of the randomised coronary artery disease patients were treated with platelet inhibitors, B-blockers, lipid lowering drugs, nitrates, Ca-blockers, diuretics and oral anticoagulants. Homogeneity was maintained between these two groups of patients.

42 Subgruppenanalyse RRR (%) Mit Lipidsenker Ohne LipidsenkerPerindopril besserPlacebo besser0,51,02,0Ohne LipidsenkerMit -BlockerOhne -BlockerMit Ca-AntagonistenOhne Ca-Antagonisten16,322,326,47,015,822,2Consistency of benefits with perindopril is shown in all patients whether they were using lipid lowering drugs, b-blockers and Calcium-channel blockers, or not. Almost all patients were using platelet inhibitors and more than half of them, lipid lowering drugs.By further analysis, no drug interaction was found meaning that benefits with perindopril are independent of other drugs.92% der Patienten erhielten Thrombozytenaggregationshemmer

44 Tödl. und nicht tödl. MI RRR: 24% p < 0,001 Plazebo Perindopril (%)246810p < 0,001RRR: 24%PlazeboPerindoprilPerindopril 8 mg once daily reduced myocardial infarction (fatal or non-fatal) by 24 % (p<0.001). This is one of the most impressive results as curves separated early and there was a tendency for the gap between curves to widen more in time even after the end of the study follow up.As Dr Harvey White, from Cardiology Dept. Green Lane hospital, NZ commented in the EUROPA editorial: “Although the blood pressure reduction in EUROPA was small (5mm Hg systolic and 2 mm Hg diastolic), the systolic pressure reduction might be expected to translate into a 10% reduction in myocardial infarction, whereas the actual reduction in non-fatal MI was 24%”. This demonstrates that BP reduction should not be the predominant mechanism of benefit with perindopril.12345Jahre

45 Hospitalisierung bei HerzinsuffizienzRRR: 39%Plazebo0,00,51,01,52,0(%)PerindoprilAnother very significant result was reduction of hospitalisation for heart failure by 39% (p=0.002). There is a clear evidence that the patients assigned to perindopril 8 mg once daily benefited right after the onset of the study.51234Jahre

46 Blutdruck Perindopril 8mg Plazebo RRsys: 5 mmHg RRdiast: 2 mmHg-1-1/236121824303642485460Monate708090100110120130140mmHgRRsys: 5 mmHgRRdiast: 2 mmHgDuring the run-in period during where all patients received perindopril, blood pressure was reduced from 137/82 to 128/78 mm Hg. After randomisation, systolic and diastolic blood pressures among patients treated with perindopril were maintained until the study end and the average blood pressure during double-blind treatment was 5/2 mm Hg higher in the placebo group. Also, it was shown that reduction of fatal and non-fatal MI was reduced more then due to the reduction of BP alone (ref. EUROPA editorial).

47 Compliance Plazebo Perindopril 8mg (%) 6 12 18 24 30 36 Monate 20 4061218243036Monate20406080100120(%)PlazeboPerindopril 8mgAfter randomisation, study medication was well tolerated. At 3 years, 81% of patients assigned perindopril and 84% of placebo patients, were taking study medication. Most of the patients assigned to perindopril continued on 8 mg, only 7% had dropped to 4 mg at 3 years. The average use of study medication was 3.7 years of 4.2 years follow-up.

48 Absetzen der BehandlungPerindopril%PlazeboHusten2.70.5Hypotonie1.00.3NiereninsuffizienzUnverträglichkeit2.41.3Studienendpunkt6.27.5Hypertonie0.40.8Verweigerung der Einnahme4.34.2Sonstige Gründe5.75.8As perindopril 8 mg once daily was very well tolerated, the reasons for permanent withdrawal from treatment were comparable to placebo.

49 Klinische Aussagen J:\artem\F151097\Europa 10/24/97Clinical implications from EUROPA trial are important for all at-risk coronary artery disease patients in the clinical practice.

50 Belastung durch KHK Weltweit 56 Mio. Todesfälle (2001)29% durch CV Erkrankungen (~ 16 Mio.)(Prognose für 2020: 37%)EU: 20 Mio. Menschen leiden unter KHKOut of 56 million deaths worldwide in 2001, burden of coronary disease is accounted for 29% of them, causing deaths in total for 16 million people. In 2020, 37% of deaths are foreseen as CV deaths.In the European Union, there are 20 million people at risk who have coronary artery disease. Prof. Kim Fox, at the EUROPA study presentation commented that “investigators were particularly excited because the disease they are talking about is the most important disease, and every improvement they can make will have a great impact on the health care in the western world.

59 Absoluter NutzenMit Perindopril 8mg 1mal täglich kann ein schweres kardiovaskuläres Ereignis(Tod, nicht tödlicher MI oder Herzstillstand)bei jedem 50. KHK-Patienten, der 4 Jahrebehandelt wird, verhindert werden.Once again, the absolute benefits were achieved with perindopril 8 mg once daily in the EUROPA trial:“Adding perindopril to standard optimal therapy over a four year period would stop 50,000 heart attacks or cardiovascular deaths in a country with a population of 60 million” concluded prof. Kim Fox, the study chairman.“The EUROPA trial provides clear evidence of major health gains for these patients. If the findings are applied worldwide then many millions of lives could be saved” added prof. Willem Remme, the study chairman.

60 Nutzen der ResultateDie Vorteile waren unabhängig von der state of the art Standardtherapie (92% Aggregations- hemmer, 58% Lipidsenker, 62% -Blocker) nach- weisbar und konsistent in allen vordefinierten Patientengruppen.Perindopril sollte zur Langzeit-Behandlungaller KHK-Patienten in Betracht gezogen werden.Last but not least, all these benefits demonstrated with perindopril 8 mg once daily in EUROPA trial, were achieved on top of standard optimal treatment (platelet inhibitors, lipid lowering drugs and ß -blockers) and are consistent in all sub-groups of patients.Perindopril should be used in chronic therapy in all patients with coronary disease:As prof. Willem Remme concluded: “We now have sufficient evidence to show that perindopril, due to its anti-atherogenic effects and blood pressure lowering properties is beneficial and should be used in treating all patients with coronary artery disease”.